The goal of the Center for Reproductive Science and Medicine at UCSD is to develop understanding of the mechanisms that govern normal and disordered function of the hypothalamic-pituitary-ovarian axis. This application represents our renewal for years 29-33. Our productivity has been outstanding with 60 papers published and 9 submitted in 3 years of a 4-year award. We will continue to produce novel, significant contributions to the reproductive sciences, integrating multidisciplinary clinical, translational, and basic research to facilitate and accelerate the translation of promising new discoveries into clinical medicine. We are proposing 3 integrated, innovative Research Projects, all with experienced, internationally renowned leaders. Project I (Pamela L. Mellon, PL) will address the hormonal control of the pituitary gonadotrope, focusing on regulation by activin, GnRH, and steroid hormones in vitro and in vivo. The emphasis will be on understanding the synergy and interdependence between these hormones in controlling transcription in model immortalized gonadotrope cells, genetically modified mice, and mouse models of precocious puberty and PCOS. Project II (Jerrold M. Olefsky, PL) will chart new territory in the role of metabolic control in fertility. A dual in vivo/in vitro approach will elucidate the mechanisms of adiponectin, SirT1, and PPAR? actions in regulating reproduction, using immortalized hypothalamic GnRH-secreting neurons and gonadotrope cells, novel genetically modified mice, and mouse models of PCOS. Project III (R. Jeffrey Chang, PL) will delineate the relative roles of specific factors implicated in excess production of androgen by the ovarian theca cell in women with PCOS and undertake studies in human ovary culture systems, addressing fundamental mechanisms underlying PCOS. All Project Leaders serve as Co-l's on other components of the Center and all 3 projects include teams of very experienced investigators. The Projects are highly interactive and synergistic, creating a coherent mechanistic and translational Center. The Administrative Core supports the Center, provides the Enrichment Program, and facilitates interactions within the Center and the SCCPIR Program. The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide.